Naphthothiopyranone derivatives

ABSTRACT

A naphthothiopyranone derivative represented by the formula: ##STR1## (wherein R 1  is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) and an acid addition salt thereof have more excellent antagonist effect at serotonin 3 receptors than the prior art compounds and the effects based thereon, e.g. anti-vomiting effect, gastrointestinal movement regulating effect and anti-anxiety effect.

DESCRIPTION

1. Technical Field

The present invention relates to naphthothiopyranone derivatives, andmore particularly relates to naphthothiopyranone derivatives having theantagonist effect of 5-HT (serotonin) at 5-HT₃ (serotonin 3) receptors.

Background Art

Compounds described in EP-A-364274 have heretofore been known as havingthe structure and effect similar to those of the compounds of thepresent invention, but they do not have a satisfactory degree of thedrug effect.

An object of the present invention is to provide compounds having moreexcellent anti-vomiting effect, gastrointestinal movement regulatingeffect and anti-anxiety effect based on the antagonist effect atserotonin 3 receptors than the prior art compounds.

DISCLOSURE OF THE INVENTION

The present invention is a naphthothiopyranone derivative represented bythe formula: ##STR2## (wherein R¹ is a hydrogen atom or an alkyl grouphaving 1 to 4 carbon atoms) or an acid addition salt thereof, andfurther a compound represented by the formula: ##STR3## which is anintermediate of the compound of Formula (I).

In the present invention, the alkyl group having 1 to 4 carbon atomsmeans a straight or branched chain alkyl group. The acid addition saltof the compound of Formula (I) means an addition salt of apharmacologically acceptable acid, for example, hydrochloride,hydrobromide, hydroiodide, sulfate, acetate, citrate, maloate, maleate,tartarate and succinate.

The compound of Formula (I) of the present invention can be prepared,for example, by the following processes.

A compound of Formula (II) is first reacted with a halogenating agent ofcommon use (e.g. hydrobromic acid, thionyl chloride, phosphoruspentachloride, thionyl bromide and phosphorus tribromide) in an organicsolvent or without solvent to give a compound represented by theformula: ##STR4## (wherein X is a halogen atom). The halogen atom hereinmeans a chlorine atom, a bromine atom or an iodine atom. Examples of theorganic solvent to be used are tetrahydrofuran, dioxane, ether, benzene,toluene, chloroform, dichloromethane, carbon tetrachloride, pyridine anda mixture of these solvents with hexamethylphosphorus triamide. A basesuch as triethylamine can also be added.

The compound obtained above is reacted with a compound represented bythe formula: ##STR5## (wherein R¹ is as defined above) or an acidaddition salt thereof in an organic solvent in the presence or absenceof a base to give a compound of Formula (I). Examples of the base to beused in the reaction are triethylamine, pyridine, potassium carbonate,sodium carbonate, lithium carbonate, cesium carbonate, sodiumbicarbonate, sodiumshydride, sodium hydroxide, potassium hydroxide,sodium ethoxide and potassium t-butoxide ("base" used hereinafter in theterm of the disclosure of the invention is the same as defined herein).Examples of the organic solvent to be used are dichloromethane,chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether,dioxane, N,N-dimethylformamide, benzene, toluene and alcohols. Inaddition, iodides (e.g. potassium iodide) or phase-transfer catalysts(e.g. tetrabutylammonium bromide) can be used as a catalyst toaccelerate the reaction.

On the other hand, the compound of Formula (II) of the intermediate is anovel compound and can be prepared, for example, by the followingprocesses.

A known compound represented by the formula: ##STR6## which can beprepared by the method described in Journal of Chemical Society, ParkinTrans. I, vol. 6, pp. 787-792 (1972), is reacted with formaldehyde inthe presence of a base in an organic solvent at from room temperature tothe boiling point of the solvent to give the compound of Formula (II).Examples of the organic solvent to be used in the reaction aretetrahydrofuran, dioxane, methanol, ethanol, isopropanol andN,N-dimethylformamide.

On the other hand, the compound of Formula (III) is reacted withformamide in the presence of a base in an organic solvent at from atemperature under ice-cooling to room temperature, and then theresulting compound represented by the formula: ##STR7## is reacted witha base to give the compound of Formula (II). Examples of the organicsolvent to be used herein are tetrahydrofuran, dioxane, methanol,ethanol, isopropanol and N,N-dimethylformamide.

The compound of Formula (I) of the present invention can be formulatedinto the dosage form such as tablets, granules, capsules, powders,pills, injections, solutions and suppositories and administered orally,directly (e.g. intramascularly and intravenously) or rectally. The abovedosage form can be prepared by using conventional fillers (e.g.crystalline cellulose, starch and lactic acid), binders (e.g.hydroxypropyl cellulose and polyvinylpyrrolidone) and lubricants (e.g.magnesium stearate and talc) according to a conventional manner (e.g.the method regulated in the Pharmacopoea of Japan, 12th Edition). Thedose of the compound of Formula (I) depends on the condition, age andbody weight of the patient, but usually the daily dose to adult may befrom 0.5 mg to 50 mg, administration being effected once or severaltimes depending on the condition.

BEST MODE OF CARRYING OUT THE INVENTION

The present invention is hereinafter illustrated in more detail by thefollowing examples and experiment.

EXAMPLE 1

2-[(4-Methyl-1-imidazolyl)methyl]-1H-naphtho-[2,1-b]thiopyran-1-one

(1) To a solution of 11.1 g of2-bromo-2,3-dihydro-1H-naphtho[2,1-b]thiopyran-1-one in 300 ml ofmethanol were added 29 ml of 35% formalin and 5.74 g of potassiumcarbonate, and stirring was continued at 60° C. for 6 hours. Afterevaporation of the methanol under reduced pressure, the residue wasdissolved in ethyl acetate, and the resulting solution was washedsuccessively with 3N hydrochloric acid, water and a saturated aqueoussodium chloride solution, and dried over anhydrous sodium sulfate.

After evaporation of the solvent under reduced pressure, purification bysilica gel column chromatography (eluant; n-hexane:ethyl acetate=5:1)and recrystallization from ethyl acetate - n-hexane gave 3.70 g of2-hydroxymethyl-1H-naphtho[2,1-b]thiopyran-1-one.

m.p. 158°-159° C.

(2) To a solution of 1.49 g of the compound obtained in the item (1) in20 ml of tetrahydrofuran and 1.6 ml of hexamethylphosphorus triamide wasadded dropwise 0.52 ml of thionyl chloride with stirring underice-cooling. Stirring was further continued at room temperature for 3hours, and the reaction solution, after addition of ice water, wasextracted with ethyl acetate. The organic layer was washed successivelywith water, a saturated aqueous sodium bicarbonate solution, water and asaturated aqueous sodium chloride solution, and dried over anhydrousmagnesium sulfate.

After evaporation of the solvent, the residue was recrystallized fromdichloromethane - n-hexane to give 1.23 g of2-chloromethyl-1H-naphtho[2,1-b]thiopyran-1-one.

m.p. 151°-153° C.

(3) To a solution of 0.30 g of the compound obtained in the item (2) and0.10 g of 4-methylimidazole in 10 ml of N,N-dimethylformamide was addedgradually 51 mg of sodium hydride (60% oil) under a nitrogen stream andice cooling with stirring, and further stirring was continued for 20minutes. The reaction solution, after addition of water, was extractedwith ethyl acetate, and the organic layer was washed successively withwater and a saturated aqueous sodium chloride solution and dried overanhydrous sodium sulfate.

After evaporation of the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluant;dichloromethane:methanol:35% ammonia water=90:10:0.5) and recrystallizedfrom dichloromethane - n-hexane to give 66 mg of the title compound.

m.p. 180°-181° C.

EXAMPLE 2

2-Hydroxymethyl-1H-naphtho[2,1-b]thiopyran-1-one obtained in Example1(1) was also prepared by another method as follows. (1) To a solutionof 64.7 g of 2-bromo-2,3-dihydro-1H-naphtho [2,1-b]thiopyran-l-one in200 ml of tetrahydrofuran were added 258 ml of 35% formalin and 32.2 gof potassium carbonate, and stirring was continued under ice cooling for1.5 hours.

After evaporation of about 100 ml of the tetrahydrofuran under reducedpressure, water was added to the residue, and the resulting crystalswere collected by filtration to give 64.3 g of 2-bromo-2-hydroxymethyl-2,3-dihydro-1H-naphtho[2,1-b]thiopyran- 1-one.

m.p. 85°-87° C.

(2) To a solution of 64.3 g of the compound obtained in the item (1) in200 ml of tetrahydrofuran was added 29.3 g of triethylamine, andstirring was continued for 1.5 hours.

After evaporation of about 100 ml of the tetrahydrofuran under reducedpressure, water was added to the residue, and the resulting crystalswere collected by filtration and recrystallized from dichloromethane -n-hexane to give 38.8 g of2-hydroxymethyl-1H-naphtho[2,1-b]thiopyran-l-one.

m.p. 156°-158° C.

EXAMPLE 3

2-[(2-Methyl-1-imidazolyl)methyl]-1H-naphtho- [2,1-b]thiopyran-1-one

To a suspension of 0.17 g of sodium hydride in 10 ml ofN,N-dimethylformamide was added 0.35 g of 2-methylimidazole under anitrogen stream and ice cooling, and stirring was continued for 20minutes. A solution of 1.0 g of the compound obtained in Example 1(2) in20 ml of N,N-dimethylformamide was added under ice cooling, and stirringwas continued for an hour. The reaction solution, after addition ofwater, was extracted with ethyl acetate, and the organic layer waswashed successively with water and a saturated aqueous sodium chloridesolution and dried over anhydrous sodium sulfate.

After evaporation of the solvent under reduced pressure, the residue waspurified by silica gel column chromatography (eluant;dichloromethane:methanol:ammonia water=90:10:0.5) and recrystallizedfrom dichloromethane - n-hexane to give 0.62 g of the title compound.

m.p. 212°-213° C. (decomposition).

EXAMPLE 4

2-[(2-Methyl-1-imidazolyl)methyl]-1H-naphtho-[2,1-b]thiopyran-1-onehydrochloride

0.1 g of 2-[(2-methyl-1-imidazolyl)methyl]-1H-naphtho[2,1-b]thiopyran-1-one obtained in Example 3, after dissolvingin methanol, was converted into the hydrochloride with conc.hydrochloric acid. After evaporation of the solvent under reducedpressure, the residue was recrystallized from methanol - diethyl etherto give 64 mg of the title compound.

m.p. 230° C. or above.

¹ H-NMR (DMSO-d₆) δ ppm:

10.00(1H, m), 8.55(1H, s), 8.28(1H, d, J=8.5Hz), 8.11(1H, m), 7.92(1H,d, J=8.5Hz), 7.68-7.83(2H, m), 7.66(1H, d, J=2Hz), 7.58(1H, d, J=2Hz),5.34(2H, s), 2.76(3H, s).

Experiment [Anti-vomiting Effect Test]

Emesis induced by cisplatin is known to be inhibited by antagonists at5-HT₃ receptors. The anti-vomiting effect of the compound of the presentinvention was compared with that of the compound described in Example ofJapanese Patent Kokai 2-209876 according to the method of Matsumoto etal [Japanese Journal of Pharmacology, vol. 48, pp. 303-306 (1988)].

Test samples

The compound obtained in Example 4 (hereinafter referred to as "CompoundA") and the compound described in Example 1 of Japanese Patent Kokai2-209876 (hereinafter referred to as "Compound B") were each suspendedin 0.4% aqueous carboxymethylcellulose solution to give test samples.

Test method

Group each of six suncus of either sex weighing 40-60 g (male) and 30-50g (female) were used. Each animal was placed with a chronic intravenouscannula 3 days before vomiting test. The samples prepared above wereorally administered in the doses of 0.03-3 mg/kg to each group of theanimals. After 45 minutes 30 mg/kg of cisplatin was administeredintravenously, and number of emesises was determined for a period of 2hours. Number of emesises for a period of 2 hours of a control grouptreated with 0.4% carboxymethylcellulose suspension alone was determinedas well.

Test results

Number of emesises obtained above was expressed as compared with 100% ofthe control, and IC₅₀ value was calculated by number of emesises.Results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                   Dose       % value to                                                                              IC.sub.50 value                               Sample     (mg/kg)    control   (μg/kg)                                    ______________________________________                                        Compound A 0.03       77.8      90.4                                                     0.3        17.0                                                               3          4.4                                                     Compound B 0.03       142.9     412.5                                                    0.3        68.6                                                               3          0.0                                                     ______________________________________                                    

INDUSTRIAL UTILIZATION

The compounds of the present invention have the antagonist effect ofserotonin at serotonin 3 recetors, and therefore are effective for theimprovement and treatment of gastrointestinal dysfunctions (e.g.dyspepsia, peptic ulcer, gastritis, reflux esophagitis and irritablecolon syndromes), symptoms accompanied by these dysfunctions, migraineand pain of trigemiral neuralgia. Particularly they are also effectivefor the treatment of nausea and vomiting caused by cancer chemotherapyand radiotherapy, arrhythmia and anxiety.

We claim:
 1. A naphthothiopranone derivative represented by the formula:##STR8## (wherein R¹ is a hydrogen atom or an alkyl group having 1 to 4carbon atoms) or an acid addition salt thereof.
 2. Thenaphthothiopyranone derivative as claimed in claim 1, wherein R¹ is ahydrogen atom.
 3. The naphthothiopyranone derivative as claimed in claim1, wherein R¹ is an alkyl group having 1 to 4 carbon atoms.
 4. Thenaphthothiopyranone derivative as claimed in claim 1, wherein R¹ is astraight chain alkyl group having 1 to 4 carbon atoms.
 5. Thenaphthothiopyranone derivative as claimed in claim 1, wherein R¹ is abranched chain alkyl group having 1 to 4 carbon atoms.
 6. Thenaphthothiopyranone derivative as claimed in claim 1, represented by theformula ##STR9##
 7. The naphthothiopyranone derivative as claimed inclaim 6, wherein R¹ is a hydrogen atom.
 8. The naphthothiopyranonederivative as claimed in claim 6, wherein R¹ is an alkyl group having 1to 4 carbon atoms.
 9. The naphthothiopyranone derivative as claimed inclaim 6, wherein the naphthiopyranone derivative is the acid additionsalt thereof.
 10. The naphthothiopyranone derivative as claimed in claim1, represented by the formula ##STR10##
 11. The naphthothiopyranonederivative as claimed in claim 10, wherein R¹ is a hydrogen atom. 12.The naphthothiopyranone derivative as claimed in claim 10, wherein R¹ isan alkyl group having 1 to 4 carbon atoms.
 13. The naphthothiopyranonederivative as claimed in claim 10, wherein the naphthiopyranonederivative is the acid addition salt thereof.
 14. Thenaphthothiopyranone derivative as claimed in claim 1, represented by theformula ##STR11##
 15. The naphthothiopyranone derivative as claimed inclaim 14, wherein R¹ is a hydrogen atom.
 16. The napthothiopyranonederivative as claimed in claim 14, wherein R¹ is an alkyl group having 1to 4 carbon atoms.
 17. The naphthothiopyranone derivative as claimed inclaim 14, wherein the naphthiopyranone derivative is the acid additionsalt thereof.
 18. The naphthothiopyranone derivative as claimed in claim1, wherein the naphthiopyranone derivative is the acid addition saltthereof, the acid being selected from the group consisting ofhydrochloride, hydrobromide, hydroiodide, sulfate, acetate, citrate,maloate, maleate, tartarate and succinate.